Lipoprotein (a) ("Lp(a)") was first identified by Blumberg, B. S., et al. (1962) J. Clin. Invest. 41: 1936-1944 and Berg, K. (1963) Acta Pathol. 59: 369-382. The structure of Lp(a) resembles that of low-density lipoprotein ("LDL") in that both share a lipid/apoprotein composition, mainly apolipoprotein B-100 ("apo B"), the ligand by which LDL binds to the LDL receptors present on the interior surfaces of arterial walls. The unique feature of Lp(a) is an additional glycoprotein, designated apoprotein(a), apo(a), which is linked to apo B by disulfide groups. The cDNA sequence of apo(a) shows a striking homology to plasminogen, with multiple repeats of kringle 4, one kringle 5, and a protease domain. The isoforms of apo(a) vary in the range of 300 to 800 kDa and differ mainly in their genetically determined number of kringle 4 structures. McLean, J. W., et al. (1987) Nature 300: 132-137. Apo(a) has no plasmin-like protease activity. Eaton, D. L., et al., (1987) Proc. Natl Acad. Sci. USA, 84: 3224-3228. Serine protease activity, however, has been demonstrated. Salonen, E., et al. (1989) EMBO J. 8: 4035-4040. Like plasminogen, Lp(a) has been shown to bind to lysine-sepharose, immobilized fibrin and fibrinogen, and the plasminogen receptor on endothelial cells. Harpel, P. C., et al. (1989) Proc. Natl. Acad. Sci. USA 86:3847-3851; Gonzalez-Gronow, M., et al. (1989) Biochemistry 28: 2374-2377; Miles, L. et al. (1989) Nature 339: 301-302; Hajjar, K. A., et al. (1989) Nature 339: 303-305. Furthermore, Lp(a) has been demonstrated to bind to other components of the arterial wall like fibronectin and glycosaminoglycans. The nature of these bindings, however, is poorly understood.
Essentially all human blood contains lipoprotein (a); however, there can a thousand-fold range in its plasma concentration between individuals. High levels of Lp(a) are associated with a high incidence of cardiovascular disease. Armstrong, V. W., et al. (1986) Atherosclerosis 62: 249-257;Dahlen, G., et al. (1986) Circulation 74: 758-765; Miles, L. A., et al. (1989) Nature 339: 301-302; Zenker, G., et al. (1986) Stroke 17: 942-945 (The term cardiovascular disease will be used hereafter as including all pathological states leading to a narrowing and/or occlusion of blood vessels throughout the body, but particularly atherosclerosis, thrombosis and other related pathological states, especially as occurs in the arteries of the heart muscle and the brain.)
It has also been suggested that Lp(a), the concentration of which increases markedly in the blood during pregnancy, may be linked to cardiovascular disease in woman. Zechner, R., et al. (1986) Metabolism 35: 333-336. It has also been observed that diabetics, many of whom suffer in some degree from atherosclerotic diseases, display greatly elevated serum levels of Lp(a). Bruckert, E., et al. (1990) JAMA 263: 35-36.
Low levels of ascorbate have also been associated with high incidences of cancer (Wright, L. C. et al. (1989) Int. J. Cancer 43: 241-244) and atherosclerosis in diabetes mellitus patients (Som, S. et al. (1981) Metabolism 30: 572-577). In all instance, serum concentrations of Lp(a) were elevated.
In addition to atherosclerosis and thrombosis in arteries Lp(a) has also been linked to stenosis of vein grafts after coronary bypass surgery. Hoff, H., et al. (1988) Circulation 77: 1238-1244. Similar problems of rapid occlusion of vessels have been observed in heart transplant patients.
For some time, general medical practice has focused on the role of LDL, the so called "bad cholesterol," in cardiovascular disease. A great many studies have been published ostensibly linking cardiovascular disease with elevated levels of LDL. As a result, most therapies for the treatment and prevention of arteriosclerosis rely on drugs and methods for the reduction of serum levels of LDLS. Such therapies have had mixed results. The efficacy of such approaches to the problem of cardiovascular disease continues to be major source of debate.
There exists a need, therefore, for a drug and therapy for reducing the binding of Lp(a) to vessel walls, for reducing the overall level of Lp(a) in the circulatory system and for promoting the deposition of existing deposits of Lp(a) on vessel walls.